Priority Research Papers:
The interplay of CDK4 and CDK6 in melanoma
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Karoline Kollmann1,*, Coralie Briand2,*, Florian Bellutti1, Nikolaus Schicher2, Stefan Blunder2, Markus Zojer1 and Christoph Hoeller2
1 Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Vienna, Austria
2 Department of Dermatology, Division of General Dermatology, Medical University Vienna, Vienna, Austria
* These authors have contributed equally to this article
Karoline Kollmann, email: [email protected]
Keywords: melanoma; CDK4; CDK6; PD0332991; angiogenesis
Received: November 21, 2018 Accepted: December 04, 2018 Published: February 15, 2019
The cyclin-dependent kinases CDK4 and CDK6 promote progression through the cell cycle, where their functions are considered to be redundant. Recent studies have identified an additional role for CDK6 in the transcriptional regulation of cancer-relevant genes such as VEGF-A and EGR1 in hematopoietic malignancies. We show that the CDK4/6 inhibitor PD0332991 causes a significant decrease in tumor growth in a xenotransplantation mouse model of human melanoma. shRNA knockdown of either CDK4 or CDK6 significantly reduces cell proliferation and impedes their migratory capacity in vitro, which translates into a strong inhibition of tumor growth in xenotransplantation experiments. CDK4/6 inhibition results not only in the pronounced reduction of cell proliferation but also in an impaired tumor angiogenesis. CDK6 knockdown in melanoma cell lines impairs VEGF-A expression and reduces the potential stimulation of endothelial cell growth. The knockdown of CDK4 ends in similar results. The effect is caused by changes of CDK6 localization, less CDK6 is detected on the VEGF-A promoter. Bioinformatic analysis of human melanoma patient data verifies the key role of CDK6 in tumor angiogenesis in melanoma. The results highlight the importance of the delicate balance between CDK4 and CDK6 in regulating the cell cycle and transcription.
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